Biological activity of Morita-Baylis-Hillman adduct homodimers in L. infantum and L. amazonensis: anti-Leishmania activity and cytotoxicity.

This study is a report on the anti-Leishmania activity of Morita-Baylis-Hillman (MBH) homodimers adducts against the promastigote and axenic amastigote forms of Leishmania (Leishmania) infantum and Leishmania (Leishmania) amazonensis and on the cytotoxicity of these adducts to human blood cells. Both studied homodimers, MBH 1 and MBH 2, showed activity against the promastigote forms of L. infantum and L. amazonensis, which are responsible for visceral and cutaneous leishmaniasis, respectively. Additionally, the homodimers presented biological activity against the axenic amastigote forms of these two Leishmania species. The adducts exhibited no hemolytic activity to human peripheral blood mononuclear cells or erythrocytes at the tested concentrations and achieved higher selectivity indices than amphotericin B. Evaluation of cell death by apoptosis revealed that the homodimers had better apoptosis/necrosis profiles than amphotericin B in the promastigote forms of both L. infantum and L. amazonensis. In conclusion, these Morita-Baylis-Hillman adducts had anti-Leishmania activity in an in vitro model and may thus be promising molecules in the search for new drugs to treat leishmaniasis.

MuDRA-Based Virtual Screening of Terpenes for Anti- Leishmania infantum Activity: In Vitro Validation and Mechanistic Insights from Molecular Docking.

Leishmaniasis, caused by Leishmania parasites, presents a major global health challenge due to limitations of existing treatments, including toxicity, side effects, drug resistance, and high costs. This study utilized the MuDRA (Multi-Descriptor Read Across) model for virtual screening to identify potential anti-Leishmania infantum compounds. A set of 15 terpenes and steroids was screened, leading to the identification of four promising candidates-lupeol, xylodiol, morolic acid, and trachyloban-18-oic acid. These compounds demonstrated significant activity in both virtual screening and in vitro assays. To elucidate their potential mechanisms of action, we conducted molecular docking and dynamics studies, which revealed stable interactions with key target enzymes, such as trypanothione reductase and 14-alpha demethylase (CYP51), crucial to the parasite's survival and pathogenesis. These findings provide valuable insights into novel mechanisms for targeting leishmaniasis, offering a promising basis for the development of new therapeutics. The integration of computational and experimental methods in this study not only advances our understanding of potential anti-leishmanial agents but also highlights the effectiveness of this approach in discovering new drugs for neglected diseases. Further in vivo studies and clinical trials will be essential to validate the therapeutic potential of these.

Selene-Ethylenelacticamides and N-Aryl-Propanamides as Broad-Spectrum Leishmanicidal Agents.

The World Health Organization classifies Leishmania as one of the 17 "neglected diseases" that burden tropical and sub-tropical climate regions with over half a million diagnosed cases each year. Despite this, currently available anti-leishmania drugs have high toxicity and the potential to be made obsolete by parasite drug resistance. We chose to analyze organoselenides for leishmanicidal potential given the reduced toxicity inherent to selenium and the displayed biological activity of organoselenides against Leishmania. Thus, the biological activities of 77 selenoesters and their N-aryl-propanamide derivatives were predicted using robust in silico models of Leishmania infantum, Leishmania amazonensis, Leishmania major, and Leishmania (Viannia) braziliensis. The models identified 28 compounds with >60% probability of demonstrating leishmanicidal activity against L. infantum, and likewise, 26 for L. amazonesis, 25 for L. braziliensis, and 23 for L. major. The in silico prediction of ADMET properties suggests high rates of oral absorption and good bioavailability for these compounds. In the in silico toxicity evaluation, only seven compounds showed signs of toxicity in up to one or two parameters. The methodology was corroborated with the ensuing experimental validation, which evaluated the inhibition of the Promastigote form of the Leishmania species under study. The activity of the molecules was determined by the IC50 value (µM); IC50 values < 20 µM indicated better inhibition profiles. Sixteen compounds were synthesized and tested for their activity. Eight molecules presented IC50 values < 20 µM for at least one of the Leishmania species under study, with compound NC34 presenting the strongest parasite inhibition profile. Furthermore, the methodology used was effective, as many of the compounds with the highest probability of activity were confirmed by the in vitro tests performed.

Synthetic hydrazones: In silico studies and in vitro evaluation of the antileishmania potential.

Bioprospecting and synthesis of strategically designed molecules have been used in the search for drugs that can be in leishmaniasis. Hydrazones (HDZ) are promising compounds with extensive biological activities. The objective of this work was to perform in silico studies of hydrazones 1-5 and to evaluate their antileishmanial, cytotoxic and macrophage immunomodulatory potential in vitro. Hydrazones were subjected to prediction and molecular docking studies. Antileishmanial protocols on promastigotes and amastigotes of Leishmania amazonensis, cytotoxicity and macrophage immunomodulatory activity were performed. Hydrazones showed a good pharmacokinetic profile and hydrazone 3 and hydrazone 5 were classified as non-carcinogenic. Hydrazone 5 obtained the best conformation with trypanothione reductase. Hydrazone 1 and hydrazone 3 obtained the best mean inhibitory concentration (IC50) values for promastigotes, 4.4-61.96 µM and 8.0-58.75 µM, respectively. It also showed good activity on intramacrophagic amastigotes, with hydrazone 1 being the most active (IC50 = 6.79 µM) with selectivity index of 56. In cytotoxicity to macrophages hydrazone 3 was the most cytotoxic (CC50 = 256.3 ± 0,04 µM), while hydrazone 4 the least (CC50 = 1055.9 ± 0.03 µM). It can be concluded that the hydrazones revealed important pharmacokinetic and toxicological properties, in addition to antileishmania potential in reducing infection and infectivity in parasitized macrophages.

Natural Products from Annonaceae as Potential Antichagasic Agents.

Chagas disease, a neglected tropical disease, is endemic in 21 Latin American countries and particularly prevalent in Brazil. Chagas disease has drawn more attention in recent years due to its expansion into non-endemic areas. The aim of this work was to computationally identify and experimentally validate the natural products from an Annonaceae family as antichagasic agents. Through the ligand-based virtual screening, we identified 57 molecules with potential activity against the epimastigote form of T. cruzi. Then, 16 molecules were analyzed in the in vitro study, of which, six molecules displayed previously unknown antiepimastigote activity. We also evaluated these six molecules for trypanocidal activity. We observed that all six molecules have potential activity against the amastigote form, but no molecules were active against the trypomastigote form. 13-Epicupressic acid seems to be the most promising, as it was predicted as an active compound in the in silico study against the amastigote form of T. cruzi, in addition to having in vitro activity against the epimastigote form.

Molluscicidal and cercaricidal activities of the essential oil of Dysphania ambrosioides (L.) Mosyakin & Clemants: Implications for the control of schistosomiasis.

Schistosomiasis is one of the most important tropical diseases. A fundamental strategy to control its spread is the use of natural products against its vectors, which are snails of the genus Biomphalaria. The present study evaluated the chemical composition, the molluscicidal and cercaricidal effects, and the ecotoxicity of the essential oil from the aerial parts of Dysphania ambrosioides (L.) Mosyakin & Clemants (DAEO). The essential oil was obtained by hydrodistillation and analyzed by gas chromatography-mass spectrometry (GC-MS). Molluscicidal and cercaricidal activities were determined by the immersion method. Environmental toxicity was assessed from bioassays using Artemia salina larvae and Danio rerio fish. DAEO presented a 0.8% yield. The GC-MS analysis revealed the predominance of hydrocarbon monoterpenes in the oil. A total of 32 constituents was identified, with α-terpinene (50.69%) being the major compound, followed by p-cymene (13.27%) and ascaridole (10.26%). DAEO was active against adult Biomphalaria glabrata snails and demonstrated lethal effect against Schistosoma mansoni cercariae, with LC50 values of 25.2 (22.7-27.8) and 62.4 (61.8-62.9) µg/mL, respectively. Regarding toxicity to non-target aquatic organisms, the oil showed LC50 values of 86.9 (84.7-87.6) and 18.6 µg/mL (15.5-22.8) for A. salina and D. rerio, respectively. DAEO proved to be a promising natural product for the control of schistosomiasis, acting on both the vectors and the etiological agent of the disease. However, the use of the oil is safer in transmission sites where there are no non-target organisms, as it has showed toxicity to D. rerio fish.

Computer-Assisted Design of Thiophene-Indole Hybrids as Leishmanial Agents.

BACKGROUND: Chemoinformatics has several applications in the field of drug design, helping to identify new compounds against a range of ailments. Among these are Leishmaniasis, effective treatments for which are currently limited. OBJECTIVE: To construct new indole 2-aminothiophene molecules using computational tools and to test their effectiveness against Leishmania amazonensis (sp.). METHODS: Based on the chemical structure of thiophene-indol hybrids, we built regression models and performed molecular docking, and used these data as bases for design of 92 new molecules with predicted pIC50 and molecular docking. Among these, six compounds were selected for the synthesis and to perform biological assays (leishmanicidal activity and cytotoxicity). RESULTS: The prediction models and docking allowed inference of characteristics that could have positive influences on the leishmanicidal activity of the planned compounds. Six compounds were synthesized, one-third of which showed promising antileishmanial activities, with IC50 ranging from 2.16 and 2.97 µM (against promastigote forms) and 0.9 and 1.71 µM (against amastigote forms), with selectivity indexes (SI) of 52 and 75. CONCLUSION: These results demonstrate the ability of Quantitative Structure-Activity Relationship (QSAR)-based rational drug design to predict molecules with promising leishmanicidal potential, and confirming the potential of thiophene-indole hybrids as potential new leishmanial agents.

In Vitro Effects of the Neolignan 2,3-Dihydrobenzofuran Against Leishmania Amazonensis.

Leishmaniasis is an infectious disease complex caused by protozoa from the Leishmania genus, which presents a broad spectrum of clinical manifestations: cutaneous, mucocutaneous and visceral forms. The current treatments are unsatisfactory considering that few drugs are available and present some level of toxicity. Many lignans and neolignans have been used for the development of new antileishmania drugs. The capability in vitro of the neolignan 2,3-dihydrobenzofuran (2,3-DBF), a commonly found constituent of propolis and other plants, to inhibit the growth of promastigote and macrophage-internalized amastigote forms of Leishmania amazonensis was investigated. The cytotoxicity of this compound was assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test in BALB/c murine macrophages and human erythrocyte lysis assay. The 2,3-DBF was active against promastigote (IC50 =1.042 µM) and amastigote (IC50 =1.43 µM) forms, indicating a potent antileishmanial effect. There was no evidence of cytotoxicity to macrophages or erythrocytes at concentrations ranging from 13 to 0.5 µM, after 48 hr of exposure. The antileishmanial activity is probably mediated by the activation of macrophages, because treatment with 2,3-DBF increases both phagocytic and lysosomal activities, as well as the nitrite (NO2- ) levels. These results suggest that 2,3-DBF may be a potential candidate for the development of a new promising antileishmanial drug. Further studies are needed to determine its potential in vivo effect as well as additional mechanisms underlying the antileishmanial and immunomodulatory activities.